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EIF2B3 (Eukaryotic Translation Initiation Factor 2B Subunit Gamma)

Written2021-01Gözde Köksal-Biçakci, Didem Naz Dioken, Ayse Elif Erson-Bensan
Department of Biological Sciences, Middle East Technical University, Ankara, TURKEY, gozdek@metu.edu.tr; didem.doken@metu.edu.tr; erson@metu.edu.tr

Abstract Eukaryotic Translation Initiation Factor 2B Subunit Gamma (EIF2B3) gene maps to 1p34.1, consists of 12 exons and 11 introns (NCBI Reference Sequence: NC_000001.11: 44850522-44986722). The locus generates three transcripts as a result of alternative splicing. EIF2B3 protein is composed of 452 amino acids and it is one of the important subunits of EIF2B decameric complex with guanine nucleotide exchange factor (GEF) activity. EIF2B3 protein plays a crucial role in the rate-limiting step of translation initiation.

Keywords EIF2B3, eukaryotic initiation factor 3 gamma, initiation factor

(Note : for Links provided by Atlas : click)

Identity

Alias (NCBI)Eukaryotic Translation Initiation Factor 2B, Subunit 3 Gamma, 58kDa; Translation Initiation Factor EIF-2B Subunit Gamma; EIF-2B GDP-GTP Exchange Factor Subunit Gamma; Eukaryotic Translation Initiation Factor 2B, Subunit 3 (Gamma, 58kD); EIF2Bgamma, eIF2Bγ.
HGNC (Hugo) EIF2B3
HGNC Alias symbEIF2Bgamma
EIF-2B
HGNC Previous nameeukaryotic translation initiation factor 2B, subunit 3 (gamma, 58kD)
 eukaryotic translation initiation factor 2B, subunit 3 gamma, 58kDa
LocusID (NCBI) 8891
Atlas_Id 62775
Location 1p34.1  [Link to chromosome band 1p34]
Location_base_pair Starts at 44850522 and ends at 44986595 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping EIF2B3.png]
Local_order Local order of the gene with the leading and subsequent genes on the first chromosome from centromere to telomere is given below (Figure 1).
 
  Local order of EIF2B3 is shown on chromosome 1. The direction of arrows indicates transcriptional direction on the chromosome and arrow sizes indicate the approximate gene sizes.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

DNA/RNA

Note EIF2B3 gene consists of 12 exons and 11 introns. The gene maps to 1p34.1 and is 136,201 bp long (NCBI Reference Sequence: NC_000001.11: 44850522-44986722). Highlighted in orange is the protein coding sequence from exons 2-12 (Figure 2).
 
  EIF2B3 gene has 12 exons and 11 introns. Numbers above indicate the exons. Orange boxes represent the exons/protein-coding regions while grey boxes represent the exons/untranslated regions.
Description EIF2B3 gene is 136,201 bp long and is on the minus strand. This gene has 12 exons.
Transcription EIF2B3 produces 3 coding mRNA transcripts (1900 bp, 1607 bp, and 1923 bp). The first transcript variant is the longest one with 12 exons. The difference between the first and the third variant is the absence of the 11th exon in the third variant resulting in a shorter transcript. The second variant lacks the last two coding exons of the first variant and is the shortest transcript variant among the three isoforms (NCBI, 2020).

Protein

Note The gene coding EIF2B3 encodes a 452 amino acid protein. This protein is a member of the subunits of initiation factor eIF2B. It has an estimated molecular weight of 50,240 kDa (Wortham et al., 2014).
 
  EIF2B3 has two functional domains; one nucleotidyl transferase domain (NT) and one acyl transferase (AT) domain. The numbers below the boxes indicate the amino acid numbers.
Description EIF2B3 protein catalyzes the exchange of GDP for GTP bound to the eukaryotic initiation factor 2. Through its highly conserved NT domain, EIF2B3 is an essential component of a decameric complex with other EIF2B subunits required for translational initiation and regulation (Pavitt, 2005). Additionally, AT domain containing hexad repeats of isoleucyl residues (also termed as I-patch region) plays a key role in the interaction of the catalytic subcomplex of the EIF2B complex with other domains (Wang et al., 2012).
Expression EIF2B3 protein is detected in almost all human tissues. The expression is mostly cytoplasmic in human tissues (The Human Protein Atlas, 2020). The protein expression for EIF2B3 is highest in pancreas, thyroid gland, and breast tissue (Samaras et al., 2019)
Localisation EIF2B3 protein localizes to the cytosol with the other proteins of the EIF2B complex (Hodgson et al., 2019).
Function EIF2B3, is one of the important subunits of the decameric complex of EIF2B with guanine nucleotide exchange factor (GEF) activity. During the initiation of translation, eukaryotic initiation factor-2, a heterotrimeric GTPase, forms a ternary complex with Met-tRNAi which is delivered to 40S ribosomal subunit (Pavitt, 2005). After the recognition of AUG codon by Met-tRNAi at the P site, eIF2-GTP is hydrolyzed resulting in the release of inactive eIF2-GDP, which aids 40S and 60S ribosomal subunit assembly (Pavitt, 2005). In this inactive state of eIF2, the initiation of new rounds of translation is not possible unless there is a switch from GTP to GDP (Mohammad-Qureshi, Jennings, & Pavitt, 2008). Hence, eIF2B activating the eIF2 by exchanging GDP for GTP with its GEF activity is a key factor for translation (Mohammad-Qureshi et al., 2008).
EIF2B has five subunits (α - ε), which form the regulatory and the catalytic sub-complexes. EIF2Bγ (EIF2B3) together with EIF2B5 (EIF2Bε) form the catalytic sub-complexes (EIF2Bcat), while EIF2B1 (EIF2Bα), EIF2B2 (EIF2Bβ), and EIF2B4 (EIF2Bδ) subunits form the regulatory sub-complexes (EIF2Breg) (Hinnebusch & Yang, 1996; Kashiwagi et al., 2016). The catalytic sub-complex is responsible for the GEF activity of the complex. Some studies suggest that eIF2Bε itself is enough for GEF activity in vitro; however, activity may be very low without EIF2B3 (Gomez, Mohammad, & Pavitt, 2002). On the contrary, another study suggests that γ and ε subunits together have the GEF function; indeed, the pyrophosphorylase-like (PL) domain of γ subunit is the main responsible part for GTP binding (Gordiyenko et al., 2014).
EIF2B3 was reported to be a cofactor for hepatitis C virus (HCV) IRES-mediated protein translation (Kruger et al., 2000).
The expression level, availability and activity eukaryotic initiation factors are usually regulated by key signaling pathways, such as phosphatidylinositol 3-kinase (PI3K)/AKT, mitogen-activated protein kinase (MAPK), and mammalian target of rapamycin (mTOR) pathways. Deregulation of these pathways may have significant effect on translation initiation through initiation factors (Hao et al., 2020).
Homology EIF2B3 gene has high homology across species, including chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, fruit fly, mosquito, C.elegans, S.pombe, M.oryzae, N.crassa, A.thaliana, rice, and frog (NCBI HomoloGene, 2020). So far, 317 orthologous genes to human EIF2B3 gene have been reported (NCBI, 2020).

Mutations

Note According to COSMIC database, 683 samples out of 37,420 unique samples from cancer patients have EIF2B3 mutations. There are 143 unique substitution mutations in 860 cancer patients for EIF2B3 gene. 14% of all the reported mutations are missense mutations (COSMIC database, 2018). Mutation burden is generally low for different cancer types, but the alteration frequency is the highest for endometrial carcinoma with 5.12% in 586 cases (cBioPortal database) (Cerami et al., 2012; Gao et al., 2013).
EIF2B3 mutations may also be related to vanishing white matter disease and ovarian failure (La Piana et al., 2012).

Implicated in

Note EIF2B3 has been implicated in leukoencephalopathies.
  
Entity Vanishing White Matter disease (VWM)/ Childhood Ataxia with Diffuse Central Nervous System Hypomyelinization (CACH)
Disease One of the most common leukoencephalopathies in children is the vanishing white matter (VWM) disease/childhood ataxia with diffuse central nervous system hypomyelination. This autosomal recessive disease is mostly common in early childhood, but it also affects adults (Zhang et al., 2015). Mutation in any of the five genes encoding the subunits of the eukaryotic translation initiation factor 2B (EIF2B), including EIF2B3, is known to be the major cause of the disease (Leegwater et al., 2001). A mutation screening on 11 Chinese patients showed that 20% of the total number of mutations found in all subunits of EIF2B mainly belongs to EIF2B3 (Wu et al., 2009). These mutations impair the EIF2B function, hence protein synthesis. Eventually, this brings the abnormalities in cerebral white matter such as demyelination of white matter, which is replaced by the cerebrospinal fluid (Fogli & Boespflug-Tanguy, 2006). Neurological deteriorations and even death may occur because of the vanishing of the white matter. Additionally, in the cases of adult-onset disease, women may experience leukoencephalopathy together with ovarian failure, which is described as ovarioleukodystrophy (Fogli et al., 2003)
Prognosis A long term follow-up study on Chinese children with VWM showed that the median survival time for patients is 8.83 ± 1.51 years (Zhang et al., 2015).
  
  
Entity Premature Ovarian Failure (POF)
Disease eIF2B mutations, described in patients with POF with white matter abnormalities, are an uncommon cause of pure spontaneous premature ovarian failure (Fogli et al., 2004).
  
  
Entity Breast Cancer
Disease PI3K/Akt/GSK-3β/ROS/eIF2B pathway might promote the growth and metastasis of breast cancer through the suppression of NK cell cytotoxicity and tumor cell susceptibility (Jin et al., 2019). The PI3K/Akt pathway inactivates GSK3B by phosphorylation at Ser9 resulting in increased ROS (reactive oxygen species). As a result of this, EIF2B phosphorylation at Ser535 is attenuated, that causes the downregulation of NKG2D (natural killer group 2 member D, a.k.a. KLRK1, killer cell lectin like receptor K1) and NKG2DL (NKG2D ligand) resulting in suppression of NK cell activity. Through this mechanism, both growth and metastasis of breast cancer is promoted in mouse (Jin et al., 2019).
  
  
Entity Endometrial Carcinoma
Disease 5.12% of samples obtained from 586 endometrial carcinoma patients have mutations in EIF2B3 gene (cBioPortal database) (Cerami et al., 2012; Gao et al., 2013).
  
  
Entity Ovarian Epithelial Tumor
Disease In addition to the mutations, the highest amplification frequency in EIF2B3 is reported in ovarian tumors in pan-cancer studies: 4.62% for 584 cases according to cBioPortal database. (Cerami et al., 2012; Gao et al., 2013).
  

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Citation

This paper should be referenced as such :
Köksal-Biçakci G, Dioken DN, Erson-Bensan AE
EIF2B3 (Eukaryotic Translation Initiation Factor 2B Subunit Gamma);
Atlas Genet Cytogenet Oncol Haematol. in press


External links

 

Nomenclature
HGNC (Hugo)EIF2B3   3259
Cards
AtlasEIF2B3ID62775ch1p34
Entrez_Gene (NCBI)EIF2B3    eukaryotic translation initiation factor 2B subunit gamma
AliasesEIF-2B; EIF2Bgamma
GeneCards (Weizmann)EIF2B3
Ensembl hg19 (Hinxton)ENSG00000070785 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000070785 [Gene_View]  ENSG00000070785 [Sequence]  chr1:44850522-44986595 [Contig_View]  EIF2B3 [Vega]
ICGC DataPortalENSG00000070785
TCGA cBioPortalEIF2B3
AceView (NCBI)EIF2B3
Genatlas (Paris)EIF2B3
SOURCE (Princeton)EIF2B3
Genetics Home Reference (NIH)EIF2B3
Genomic and cartography
GoldenPath hg38 (UCSC)EIF2B3  -     chr1:44850522-44986595 -  1p34.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)EIF2B3  -     1p34.1   [Description]    (hg19-Feb_2009)
GoldenPathEIF2B3 - 1p34.1 [CytoView hg19]  EIF2B3 - 1p34.1 [CytoView hg38]
ImmunoBaseENSG00000070785
Genome Data Viewer NCBIEIF2B3 [Mapview hg19]  
OMIM603896   606273   
Gene and transcription
Genbank (Entrez)AF257077 AK022399 AK024006 AK314668 AL834288
RefSeq transcript (Entrez)NM_001166588 NM_001261418 NM_020365
Consensus coding sequences : CCDS (NCBI)EIF2B3
Gene ExpressionEIF2B3 [ NCBI-GEO ]   EIF2B3 [ EBI - ARRAY_EXPRESS ]   EIF2B3 [ SEEK ]   EIF2B3 [ MEM ]
Gene Expression Viewer (FireBrowse)EIF2B3 [ Firebrowse - Broad ]
GenevisibleExpression of EIF2B3 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)8891
GTEX Portal (Tissue expression)EIF2B3
Human Protein AtlasENSG00000070785-EIF2B3 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9NR50   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9NR50  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9NR50
PhosPhoSitePlusQ9NR50
Domains : Interpro (EBI)MobA-like_NTP_Trfase    Nucleotide-diphossugar_trans   
Domain families : Pfam (Sanger)NTP_transf_3 (PF12804)   
Domain families : Pfam (NCBI)pfam12804   
Conserved Domain (NCBI)EIF2B3
PDB (RSDB)6CAJ    6EZO    6K71    6K72    6O81    6O85    6O9Z   
PDB Europe6CAJ    6EZO    6K71    6K72    6O81    6O85    6O9Z   
PDB (PDBSum)6CAJ    6EZO    6K71    6K72    6O81    6O85    6O9Z   
PDB (IMB)6CAJ    6EZO    6K71    6K72    6O81    6O85    6O9Z   
Structural Biology KnowledgeBase6CAJ    6EZO    6K71    6K72    6O81    6O85    6O9Z   
SCOP (Structural Classification of Proteins)6CAJ    6EZO    6K71    6K72    6O81    6O85    6O9Z   
CATH (Classification of proteins structures)6CAJ    6EZO    6K71    6K72    6O81    6O85    6O9Z   
SuperfamilyQ9NR50
AlphaFold pdb e-kbQ9NR50   
Human Protein Atlas [tissue]ENSG00000070785-EIF2B3 [tissue]
HPRD09379
Protein Interaction databases
DIP (DOE-UCLA)Q9NR50
IntAct (EBI)Q9NR50
BioGRIDEIF2B3
STRING (EMBL)EIF2B3
ZODIACEIF2B3
Ontologies - Pathways
QuickGOQ9NR50
Ontology : AmiGOcytoplasmic translational initiation  translation initiation factor activity  guanyl-nucleotide exchange factor activity  guanyl-nucleotide exchange factor activity  protein binding  cytoplasm  cytosol  eukaryotic translation initiation factor 2B complex  eukaryotic translation initiation factor 2B complex  translational initiation  translation factor activity, RNA binding  response to heat  response to heat  response to glucose  oligodendrocyte development  hippocampus development  guanyl-nucleotide exchange factor complex  response to peptide hormone  regulation of catalytic activity  T cell receptor signaling pathway  
Ontology : EGO-EBIcytoplasmic translational initiation  translation initiation factor activity  guanyl-nucleotide exchange factor activity  guanyl-nucleotide exchange factor activity  protein binding  cytoplasm  cytosol  eukaryotic translation initiation factor 2B complex  eukaryotic translation initiation factor 2B complex  translational initiation  translation factor activity, RNA binding  response to heat  response to heat  response to glucose  oligodendrocyte development  hippocampus development  guanyl-nucleotide exchange factor complex  response to peptide hormone  regulation of catalytic activity  T cell receptor signaling pathway  
Pathways : BIOCARTAVEGF, Hypoxia, and Angiogenesis [Genes]   
REACTOMEQ9NR50 [protein]
REACTOME PathwaysR-HSA-72731 [pathway]   
NDEx NetworkEIF2B3
Atlas of Cancer Signalling NetworkEIF2B3
Wikipedia pathwaysEIF2B3
Orthology - Evolution
OrthoDB8891
GeneTree (enSembl)ENSG00000070785
Phylogenetic Trees/Animal Genes : TreeFamEIF2B3
Homologs : HomoloGeneEIF2B3
Homology/Alignments : Family Browser (UCSC)EIF2B3
Gene fusions - Rearrangements
Fusion : QuiverEIF2B3
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerEIF2B3 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)EIF2B3
dbVarEIF2B3
ClinVarEIF2B3
MonarchEIF2B3
1000_GenomesEIF2B3 
Exome Variant ServerEIF2B3
GNOMAD BrowserENSG00000070785
Varsome BrowserEIF2B3
ACMGEIF2B3 variants
VarityQ9NR50
Genomic Variants (DGV)EIF2B3 [DGVbeta]
DECIPHEREIF2B3 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisEIF2B3 
Mutations
ICGC Data PortalEIF2B3 
TCGA Data PortalEIF2B3 
Broad Tumor PortalEIF2B3
OASIS PortalEIF2B3 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICEIF2B3  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DEIF2B3
Mutations and Diseases : HGMDEIF2B3
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
BioMutaEIF2B3
DgiDB (Drug Gene Interaction Database)EIF2B3
DoCM (Curated mutations)EIF2B3
CIViC (Clinical Interpretations of Variants in Cancer)EIF2B3
Cancer3DEIF2B3
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM603896    606273   
Orphanet17140    17141    17139    14426    14427   
DisGeNETEIF2B3
MedgenEIF2B3
Genetic Testing Registry EIF2B3
NextProtQ9NR50 [Medical]
GENETestsEIF2B3
Target ValidationEIF2B3
Huge Navigator EIF2B3 [HugePedia]
ClinGenEIF2B3
Clinical trials, drugs, therapy
MyCancerGenomeEIF2B3
Protein Interactions : CTDEIF2B3
Pharm GKB GenePA27690
PharosQ9NR50
Clinical trialEIF2B3
Miscellaneous
canSAR (ICR)EIF2B3
HarmonizomeEIF2B3
DataMed IndexEIF2B3
Probes
Litterature
PubMed61 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
EVEXEIF2B3
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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